DESCRIPTION (Applicant's abstract): This research proposal addresses the mechanism of action of antidepressants. Specifically, it seeks to determine whether the 5HT1B and 5HT1A receptors are required in specific tissues for the antidepressant effects of selective serotonin reuptake inhibitors (SSRIs). In the first aim, we will extend previous experiments showing a requirement for 5HT1B receptors in the antidepressant effects of SSRIs in the forced swim test, a test of behavioral despair. We will use tissue specific knockouts of the mouse 5HT1B and 5HT1A receptors to test their role in this assay in the basal ganglia and hippocampus. In the second aim, we will use similar methods to investigate the role of 5HT1B and 5HT1A receptors in a stress protective assay of SSRI function. In the final aim, we will attempt to define the role of these receptors in a test of chronic SSRI function, a model of antidepressant action more closely mimicking their function in humans.